Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor
Tissue-specific emergence of regulatory and intraepithelial T cells from a clonal T cell precursor
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DOI：
10.1126/sciimmunol.aaf7471
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发表时间：
2016-08-01
影响因子：
24.8
通讯作者：
Ploegh, Hidde L.
中科院分区：
文献类型：
--
作者：
Bilate, Angelina M.;Bousbaine, Djenet;Ploegh, Hidde L.
外周Foxp3（+）调节性T细胞（pT（+））通过控制对饮食和微生物抗原的潜在有害效应T细胞应答来维持免疫稳态。尽管T细胞受体（TCR）的身份可以强加T细胞的定型和功能特化，但关于TCR身份如何支配常规CD4（+）T细胞的pT（reg）发育的知之甚少。为了研究TCR身份决定pT（reg）命运的程度，我们使用体细胞核转移来产生携带来自pT（reg）的单克隆TCR的跨核（TN）小鼠（pT（reg）TN小鼠）。我们发现，pT（reg）TCR并不必然使T细胞倾向于变成pT（reg），而是允许小肠中的非炎性CD4（+）CD8 α α（+）上皮内淋巴细胞（CD4（IEL））分化。只有当我们限制携带TN pT（reg）TCR的T细胞前体的数量时，我们才观察到混合骨髓嵌合体的肠系膜淋巴结和小肠固有层中大量的pT（reg）发育。小克隆大小，因此减少克隆内竞争所需的pT（reg）的发展。尽管具有相同的TCR，小肠CD4（IEL）的发展独立于前体频率。pT（reg）和CD4（IEL）的发展严格依赖于常驻微生物群。因此，单个克隆的CD4（+）T细胞前体可以以微生物群依赖的方式产生两种功能上不同且解剖学上分离的T细胞亚群。因此，CD4 T细胞区室的可塑性不仅取决于微生物群，还取决于不同组织提供的特定环境线索。
Peripheral Foxp3(+) regulatory T cells (pT(regs)) maintain immune homeostasis by controlling potentially harmful effector T cell responses toward dietary and microbial antigens. Although the identity of the T cell receptor (TCR) can impose commitment and functional specialization of T cells, less is known about how TCR identity governs pT(reg) development from conventional CD4(+) T cells. To investigate the extent to which TCR identity dictates pT(reg) fate, we used somatic cell nuclear transfer to generate a transnuclear (TN) mouse carrying a monoclonal TCR from a pT(reg) (pT(reg) TN mice). We found that the pT(reg) TCR did not inevitably predispose T cells to become pT(reg) but instead allowed for differentiation of noninflammatory CD4(+)CD8 alpha alpha(+) intraepithelial lymphocytes (CD4(IELs)) in the small intestine. Only when we limited the number of T cell precursors that carried the TN pT(reg) TCR did we observe substantial pT(reg) development in the mesenteric lymph nodes and small intestine lamina propria of mixed bone marrow chimeras. Small clonal sizes and therefore decreased intraclonal competition were required for pT(reg) development. Despite bearing the same TCR, small intestine CD4(IEL) developed independently of precursor frequency. Both pT(reg) and CD4(IEL) development strictly depended on the resident microbiota. A single clonal CD4(+) T cell precursor can thus give rise to two functionally distinct and anatomically segregated T cell subsets in a microbiota-dependent manner. Therefore, plasticity of the CD4 T cell compartment depends not only on the microbiota but also on specialized environmental cues provided by different tissues.